Posts tagged brain

March 21, 2012

What characterizes many people with depression, schizophrenia and some other mental illnesses is anhedonia: an inability to gain pleasure from normally pleasurable experiences.

This image shows VTA dopamine neurons (in red) and VTA GABA fibers (in green). Credit: Stuber Lab, UNC-Chapel Hill.

Exactly why this happens is unclear. But new research led by neuroscientists at the University of North Carolina at Chapel Hill School of Medicine may have literally shined a light on the answer, one that could lead to the discovery of new mental health therapies. A report of the study appears March 22 in the journal Neuron.

The study used a combination of genetic engineering and laser technology to manipulate the wiring of a specific population of brain cells deep in a portion of a midbrain area that’s known to promote behavioral responses to reward.

"For many years it’s been known that dopamine neurons in the ventral midbrain, the ventral tegmental area, or VTA, are involved in reward processing and motivation. For example, they’re activated during exposure to drugs of abuse and to naturally rewarding experiences," said study lead author Garret D. Stuber, PhD, assistant professor in the departments of Psychiatry and Cell and Molecular Physiology, and the UNC Neuroscience Center.

"The major focus in our lab is to determine what other sorts of neural circuits or genetically defined neural populations might be modulating the activity of those neurons, whether it’s increasing or decreasing their activity," Stuber said. "In our study we found that activation of the nearby VTA GABAergic neurons directly inhibit the function of dopamine neurons, which is something that’s never been shown before."

In the past, researchers have tried to get a glimpse into the inner workings of the brain using electrical stimulation or drugs, but those techniques couldn’t quickly and specifically change only one type of cell or one type of connection. But optogenetics, a technique that emerged about six years ago, can. 

In this study, the scientists used a transgenic animal with a foreign gene that has been inserted into its genome to express a bacterial enzyme that can cause DNA recombination only in GABA neurons and not dopamine cells. Using a gene transfer method developed at UNC and with the animal anesthetized, the Stuber team transferred light-sensitive proteins called “opsins” – derived from algae or bacteria that need light to grow – into the VTA, targeting GABA cells. The presence of these foreign opsins in GABA neurons allows researchers to excite or inhibit them by pumping light from a laser into brain tissue.

The animals were then tested in different reward situations, simple tasks in which they were trained to associate a cue with a sugar water reward from a bottle or were given the opportunity to drink the reward by “free licking,” where they could drink as much as they want.

Then, via optical fibers, the researchers shined laser beams onto the genetically manipulated GABA neurons, activating them for 5 seconds during the cue period followed by reward. And on another day, they activated the neurons during reward consumption, when the animals were actively engaged in drinking the sugar water.

"And what we saw when we activated the cells during the cue period, or reward anticipation, it didn’t do anything to the behavioral response at all; they showed no difference compared to non-stimulated animals," Stuber explained.

"And when they were actively engaging with the sucrose, we did see we could disrupt their reward consumption when we activated those cells. They immediately disengaged from drinking, stopped drinking the sucrose solution. And when the stimulus stopped, they would then return back and continue to drink it again."

During the “free licking” sessions, optical stimulation of GABA neurons resulted in disruption of sucrose consumption. The animals stopped drinking.

Using sophisticated electrophysiology and cell chemistry measures, the study team could monitor the activity of the GABA and dopamine neurons. They found a direct link between GABA activation and dopamine suppression.

"So basically, it appears that these GABA neurons located in the VTA are just microns away from dopamine and are negative regulators of dopamine function," Stuber proposes.

"When they become active, their basic job is to suppress dopamine release. A dysfunction in these GABA neurons might potentially underlie different aspects of neuropsychiatric illness, such as depression. Thus, we could think of them as a new physiological target for various aspects of neuropsychiatric diseases."

Provided by University of North Carolina School of Medicine

March 21, 2012

Investigators at the Stanford University School of Medicine have shown that removing a matched set of molecules that typically help to regulate the brain’s capacity for forming and eliminating connections between nerve cells could substantially aid recovery from stroke even days after the event. In experiments with mice, the scientists demonstrated that when these molecules are not present, the mice’s ability to recover from induced strokes improved significantly.

Importantly, these beneficial effects grew over the course of a full week post-stroke, suggesting that, in the future, treatments such as drugs designed to reproduce the effects in humans might work even if given as much as several days after a stroke occurs. The only currently available stroke treatment — tissue plasminogen activator, or tPA — must be given within a few hours of a stroke to be effective, and patients’ brains must first be scanned to determine whether this treatment is appropriate. Moreover, while tPA limits the initial damage caused by a stroke, it doesn’t help the brain restore or replace lost connections between nerve cells, which is essential to recovery.

The mice in the study had been genetically bioengineered to lack certain molecules that one of the Stanford researchers had previously shown to play a major role in modulating the ease with which key nerve-cell connections are made, strengthened, weakened or destroyed in the brain. The molecules in question include “K” and “D,” two of the 50 or so members of the so-called MHC class-1 complex, which plays a key role in the function of the immune system. Alternatively, when a receptor called PirB, which binds to these MHC molecules, is not present, the same improved outcome from stroke happens — significant, because receptors make good drug targets.

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March 20, 2012

A personality profile marked by overly gregarious yet anxious behavior is rooted in abnormal development of a circuit hub buried deep in the front center of the brain, say scientists at the National Institutes of Health. They used three different types of brain imaging to pinpoint the suspect brain area in people with Williams syndrome, a rare genetic disorder characterized by these behaviors. Matching the scans to scores on a personality rating scale revealed that the more an individual with Williams syndrome showed these personality/temperament traits, the more abnormalities there were in the brain structure, called the insula.

The severity of abnormalities in insula (red structure near bottom of brain), gray matter volume (left) and brain activity (right) predicted the extent of aberrant personality traits in Williams syndrome patients — as reflected in their scores (red dots) on personality rating scales (WSPP). Credit: Karen Berman, M.D., NIMH Clinical Brain Disorders Branch

"Scans of the brain’s tissue composition, wiring, and activity produced converging evidence of genetically-caused abnormalities in the structure and function of the front part of the insula and in its connectivity to other brain areas in the circuit," explained Karen Berman, M.D., of the NIH’s National Institute of Mental Health (NIMH).

Berman, Drs. Mbemda Jabbi, Shane Kippenham, and colleagues, report on their imaging study in Williams syndrome online in the journal Proceedings of the National Academy of Sciences.

"This line of research offers insight into how genes help to shape brain circuitry that regulates complex behaviors – such as the way a person responds to others – and thus holds promise for unraveling brain mechanisms in other disorders of social behavior," said NIMH Director Thomas R. Insel, M.D.

Long distance connections, white matter, between the insula and other parts of the brain are aberrant in Williams syndrome. Neuronal fibers of normal controls (left) extend further than those of Williams syndrome patients (right). Picture shows diffusion tensor imaging data from each patient superimposed on anatomical MRI of the median patient. Credit: Karen Berman, M.D., NIMH Clinical Brain Disorders Branch

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March 19th, 2012

Stowers researchers present a new model for how the brain is organized to process odor information.

Glomeruli in the olfactory bulb (shown in green), the first waystation for incoming olfactory signals, plays an important role in the processing and identification of smells. Image adapted from press release image courtesy of Limei Ma, Stowers Institute for Medical Research.

Just like a road atlas faithfully maps real-world locations, our brain maps many aspects of our physical world: Sensory inputs from our fingers are mapped next to each other in the somatosensory cortex; the auditory system is organized by sound frequency; and the various tastes are signaled in different parts of the gustatory cortex.

The olfactory system was believed to map similarly, where groups of chemically related odorants – amines, ketones, or esters, for example – register with clusters of cells that are laid out next to each other. When researchers at the Stowers Institute for Medical Research traced individual odor molecules’ signal deep into the brain, they found evidence that this “chemotopic” hypothesis of olfaction is insufficient, paving the way for a new model of how the sense of smell works, and how it came about.

“When we mapped the individual chemical features of different odorants, they mapped all over the olfactory bulb, which processes incoming olfactory information,” says Associate Investigator C. Ron Yu, PhD, who led the study published in this week’s online edition of the Proceedings of the National Academy of Sciences. “From the animal’s perspective that makes perfect sense. The chemical structure of an odor molecule is not what’s important to them. They really just want to learn about their environment and associate olfactory information with food or other relevant information.”

The brain receives information about odors from olfactory receptors, which are embedded in the membrane of sensory neurons in the nasal cavity. Any time an odor molecule interacts with a receptor, an electrical signal travels to so-called glomeruli in the olfactory bulb. Each glomerulus receives input from olfactory receptor neurons expressing only one type of olfactory receptor. The overall glomerular activation patterns within the olfactory bulb are thought to represent specific odors.

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March 19, 2012

Cerebral edemas are accumulations of fluid into the intra- or extracellular spaces of the brain and it can result from several factors such as stroke or head trauma, among others.

Cerebral edema is a serious problem in neurology. While in other organs swelling does not lead to an urgent situation, in the brain it leads to coma and death. Although there are therapeutic solutions such as surgery, more effective treatments are needed.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy (affects the white matter) of genetic origin. MLC can be considered as a model of chronic edema, as patients suffering from birth a high accumulation of water.

A study of the pathophysiology of this rare disease has uncovered one mechanism that destabilizes the homeostatic balance of brain cells causing edema. This study is published in the latest issue of the journal Neuron. The journal accompanies the paper with a commentary of the editor and an explanatory video on its website.

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Researchers from IDIBELL, the University of Barcelona (UB) and CIBERER (Spanish Network Research Centre on Rare Diseases) have found that one function of the protein GlialCAM, which is genetically altered in patients with MLC, is to regulate the activity of the channel that allows the passage of chloride ions between brain cells to regulate ion and fluid balance.

When this protein is lacked, the channel is not working properly and the fluid builds up in the brain glial cells forming edema.

Raul Estevez, director of this work, and Virginia Nunes, a partner of the study, believe that the importance of this finding is twofold. “On one hand”, explains Virginia Nunes, “it allows us to better understand the pathophysiology of this disease minority” and “on the other hand”, Raul Estevez continues, “we have identified a mechanism that can open doors to treatments based on the activation of this channel to restore homeostatic balance and perhaps treat brain edema in general.”

Both researchers agree to say that this case demonstrates that the investigation of a rare disease that affects a small proportion of the population can serve as a model to identify mechanisms to think of new treatments for common diseases.

MLC Leukodistophy

Megalencephalic Leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy that appears during the first year of life, characterized by macrocephaly (oversized head). A few years later, it appears a slow neurological deterioration with ataxia (lack of motor coordination) and spasms. Magnetic resonance techniques revealed inflammation of the cerebral white matter and subcortical cysts, particularly in the anterior temporal regions.

In the 75% of MLC patients it has been identified mutations in the gene MLC1, which cause the disease. Virginia Nunes and Raul Estevez have recently identified a second gene causing MLC, named GlialCAM.

In the present study they have been identified precisely a GlialCAM protein as an ion channel subunit chloride that allows its entering and exiting the brain so that the cells can regulate the homeostatic balance.

Provided by IDIBELL-Bellvitge Biomedical Research Institute

Source: medicalxpress.com

March 19, 2012

University of Alberta led research may have discovered how memories are encoded in our brains.

Scientists understand memory to exist as strengthened synaptic connections among neurons. However components of synaptic membranes are relatively short-lived and frequently re-cycled while memories can last a lifetime.

Based on this information, U of A physicist and lead researcher Jack Tuszynski, his graduate student Travis Craddock and University of Arizona professor Stuart Hameroff investigated the molecular mechanism of memory encoding in neurons.

The team looked into structures at the cytoskeletal level of brain structure. They found components that fit together and were capable of creating the information processing and storage capacity that the brain needs to form and retain memory.

The practical implications of understanding the mechanism of memory encoding are enormous.

"This could open up amazing new possibilities of dealing with memory loss problems, interfacing our brains with hybrid devices to augment and ‘refresh’ our memories," says Tuszynski. "More importantly, it could lead to new therapeutic and preventive ways of dealing with neurological diseases such as Alzheimer’s and dementia, whose incidence is growing very rapidly these days."

Provided by University of Alberta

Source: medicalxpress.com

March 19, 2012

Patients with relapsing onset Multiple Sclerosis (MS) who consumed alcohol, wine, coffee and fish on a regular basis took four to seven years longer to reach the point where they needed a walking aid than people who never consumed them. However the study, published in the April issue of the European Journal of Neurology, did not observe the same patterns in patients with progressive onset MS.

The authors say that the findings suggest that different mechanisms might be involved in how disability progresses in relapsing and progressive onset MS.

Researchers asked patients registered with the Flemish MS Society to take part in a survey, which included questions on themselves, their MS and their current consumption of alcohol, wine, coffee, tea, fish and cigarettes.

The 1,372 patients who agreed to take part were also asked to indicate whether they had reached stage six on the zero to ten stage Expanded Disability Status Scale (EDSS) and, if so, when this had happened.

"MS is a chronic, often disabling disease that attacks the central nervous system" explains lead author Dr Marie D’hooghe from the National MS Center at Melsbroek, Belgium. "The clinical symptoms, progression of disability and severity of MS are unpredictable and vary from one person to another.

"Two major MS onset types can be distinguished. Progressive onset MS is characterised by a gradual worsening of neurological function from the beginning, whereas patients with relapsing onset MS patients experience clearly defined attacks of worsening neurologic function with partial or full remission.

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March 19, 2012

An antioxidant combination of vitamin E, vitamin C and α-lipoic acid (E/C/ALA) was not associated with changes in some cerebrospinal fluid biomarkers related to Alzheimer disease in a randomized controlled trial, according to a study published Online First by Archives of Neurology.

Oxidative damage in the brain is associated with aging and is widespread in Alzheimer disease (AD) patients. Some observational studies have suggested that an antioxidant-rich diet may reduce the risk of AD, but antioxidant randomized clinical trials in AD have had mixed results, the authors write in their study background.

Douglas R. Galasko, M.D., of the University of California, San Diego, and colleagues examined changes in cerebrospinal fluid (CSF) biomarkers related to Alzheimer disease and oxidative stress, cognition and function.

The study included 78 patients from the Alzheimer’s Disease Cooperative Study (ADCS) Antioxidant Biomarker study who were divided into one of three groups: 800 IU/per day of vitamin E (α-tocopherol) plus 500 mg/per day of vitamin C plus 900 mg/per day of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q (CoQ) three times a day; or placebo. Sixty-six patients provided serial CSF specimens adequate for biochemical analyses during the 16-week trial.

"The combination of E/C/ALA did not affect CSF biomarkers related to Αβ, tau or P-tau (which are related to AD)," the authors comment.

The E/C/ALA group did see a lowering of CSF F2-isoprostane levels suggesting a reduction of oxidative stress in the brain, the results indicate. However, the treatment raised caution about faster cognitive decline as assessed by the Mini-Mental State Examination (MMSE).

"It is unclear whether the relatively small reduction in CSF F2-isoprostane level seen in this study may lead to clinical benefits in AD. The more rapid MMSE score decline raises a caution and indicates that cognitive performance would need to be assessed if a longer-term clinical trial of this antioxidant combination is considered," the authors conclude.

The authors also note the results indicate that while CoQ was safe and well tolerated in patients, the absence of a biomarker signal in CSF suggests that CoQ, at the tested dose, does not improve indices of oxidative stress or neurodegeneration.

"These results do not support further clinical trial development of CoQ in AD," the researchers conclude.

Provided by JAMA and Archives Journals

Source: medicalxpress.com

ScienceDaily (Mar. 19, 2012) — Researchers from Chalmers and the University of Gothenburg have shown that nanocellulose stimulates the formation of neural networks. This is the first step toward creating a three-dimensional model of the brain. Such a model could elevate brain research to totally new levels, with regard to Alzheimer’s disease and Parkinson’s disease, for example.

Nerve cells growing on a three-dimensional nanocellulose scaffold. One of the applications the research group would like to study is destruction of synapses between nerve cells, which is one of the earliest signs of Alzheimer’s disease. Synapses are the connections between nerve cells. In the image, the functioning synapses are yellow and the red spots show where synapses have been destroyed. (Credit: Illustration: Philip Krantz, Chalmers)

Over a period of two years the research group has been trying to get human nerve cells to grow on nanocellulose.

"This has been a great challenge," says Paul Gatenholm, Professor of Biopolymer Technology at Chalmers.‟Until recently the cells were dying after a while, since we weren’t able to get them to adhere to the scaffold. But after many experiments we discovered a method to get them to attach to the scaffold by making it more positively charged. Now we have a stable method for cultivating nerve cells on nanocellulose."

When the nerve cells finally attached to the scaffold they began to develop and generate contacts with one another, so-called synapses. A neural network of hundreds of cells was produced. The researchers can now use electrical impulses and chemical signal substances to generate nerve impulses, that spread through the network in much the same way as they do in the brain. They can also study how nerve cells react with other molecules, such as pharmaceuticals.

The researchers are trying to develop ‟artificial brains,” which may open entirely new possibilities in brain research and health care, and eventually may lead to the development of biocomputers. Initially the group wants to investigate destruction of synapses between nerve cells, which is one of the earliest signs of Alzheimer’s disease. For example, they would like to cultivate nerve cells and study how cells react to the patients’ spinal fluid.

In the future this method may be useful for testing various pharmaceutical candidates that could slow down the destruction of synapses. In addition, it could provide a better alternative to experiments on animals within the field of brain research in general.

The ability to cultivate nerve cells on nanocellulose is an important step ahead since there are many advantages to the material.

‟Pores can be created in nanocellulose, which allows nerve cells to grow in a three-dimensional matrix. This makes it extra comfortable for the cells and creates a realistic cultivation environment that is more like a real brain compared with a three-dimensional cell cultivation well,” says Paul Gatenholm.

Paul Gatenholm says that there are a number of new biomedical applications for nanocellulose. He is currently also leading other projects that use the material, for example a project where researchers are using nanocellulose to develop cartilage to create artificial outer ears. His research group has previously developed artificial blood vessels made of nanocellulose, which are being evaluated in pre-clinical studies.

Research on new application areas for nanocellulose is of major strategic significance for Sweden. Several projects are financed by the Knut and Alice Wallenberg Foundation and being conducted in collaboration between Chalmers and KTH within the Wallenberg Wood Science Center, WWSC.

Facts about nanocellulose: Nanocellulose is a material that consists of nanosized cellulose fibers. Typical dimensions are widths of 5 to 20 nanometers and lengths of up to 2,000 nanometers. Nanocellulose can be produced by bacteria that spin a close-meshed structure of cellulose fibers. It can also be isolated from wood pulp through processing in a high-pressure homogenizer.

Source: Science Daily

March 16, 2012 By Anne Trafton 

Alan Jasanoff. Credit: Allegra Boverman

After finishing his PhD in molecular biophysics, Alan Jasanoff decided to veer away from that field and try looking into some of the biggest questions in neuroscience: How do we perceive things? What happens in our brains when we make decisions?

After a few months, however, he realized that he didn’t have the tools he wanted to use — so he decided to start making his own.

Jasanoff, who recently earned tenure in MIT’s Department of Biological Engineering, now specializes in developing novel brain-imaging agents that can reveal information more detailed than other human brain-imaging techniques such as fMRI and PET, and more comprehensive than traditional neuroscience measurements such as microscopy and electrode recordings. With the new tools, he is also beginning to explore some of the fundamental questions that first drew him into neuroscience.

Neuroscientists commonly use fMRI, which measures blood flow in the brain, as a proxy for neural activity. In the past several years, Jasanoff has developed sensors that can be used with fMRI to image brain activity more directly, by measuring levels of neurotransmitters (the chemicals that carry messages between neurons) and calcium, which enters neurons when they fire.

Using those sensors, Jasanoff has started exploring how positive reinforcement influences behavior and decision making in animals. His work could also be applicable to fields outside of neuroscience, because intracellular signaling molecules such as calcium “are really ubiquitous — not just in neuronal signaling but signaling throughout the body, during development, immune-cell activity and so on,” says Jasanoff, who is an associate member of MIT’s McGovern Institute for Brain Research and an associate professor of biological engineering, nuclear science and engineering, and brain and cognitive sciences.

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